REVIEWS Fertile ground: human endometrial programming and lessons in health and disease Jemma Evans1–3, Lois A. Salamonsen1,2,4, Amy Winship1,2, Ellen Menkhorst1,2, Guiying Nie1,2,5, Caroline E. Gargett4,6 and Eva Dimitriadis1,2,7 Abstract | The human endometrium is a highly dynamic tissue that is cyclically shed, repaired, regenerated and remodelled, primarily under the orchestration of oestrogen and progesterone, in preparation for embryo implantation Humans are among the very few species that menstruate and that, consequently, are equipped with unique cellular and molecular mechanisms controlling these cyclic processes Many reproductive pathologies are specific to menstruating species, and studies in animal models rarely translate to humans Abnormal remodelling and regeneration of the human endometrium leads to a range of reproductive complications Furthermore, the processes regulating endometrial remodelling and implantation, including those controlling hormonal impact, breakdown and repair, stem/progenitor cell activation, inflammation and cell invasion have broad applications to other fields This Review presents current knowledge regarding the normal and abnormal function of the human endometrium The development of biomarkers for prediction of uterine diseases and pregnancy disorders and future avenues of investigation to improve fertility and enhance endometrial function are also discussed Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, 3168, Australia Department of Molecular and Translational Medicine, Monash University, Clayton, 3800, Australia Department of Physiology, Monash University, Clayton, 3800, Australia Department of Obstetrics and Gynaecology, Monash University, Clayton, 3800, Australia Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Australia The Ritchie Centre, Hudson Institute of Medical Research, Clayton, 3168, Australia Department of Anatomy and Developmental Biology, Monash University, Clayton, 3800, Australia Correspondence to E.D evdokia.dimitriadis@hudson org.au doi:10.1038/nrendo.2016.116 Published online 22 Jul 2016 The transformative processes that prepare the endometrium for embryo implantation are unique to menstruating species, and are thought to underlie the evolution of menstruation Although rodent species, which are easy to manipulate, are common experimental models for studies of endometrial receptivity and embryo implantation, findings obtained with these animals often cannot be directly translated to humans Biological processes that have developed in the human endometrium during the evolution of menstruation are specialized versions of processes that are found in other tissues, altered to regulate endometrial biology Understanding how the human endometrium undergoes controlled and spatially limited tissue destruction, resolution of inflammation, scar-free repair and re‑ epithelialization followed by regeneration and transformation can inform our understanding of processes that occur in other tissues In this Review, we describe the remodelling of the endometrium before it becomes receptive for embryo implantation, the dynamic fetal–maternal communication that contributes to successful implantation, the endometrial defects that result in infertility and miscarriage and the detection and treatment of these disorders We also identify missing links, both experimental and clinical, which should be investigated to enable progress in the field, and areas where understanding of endometrial biology might influence other fields and the develop­ment of therapeutics Evolution of human menstruation Unlike other organs, the human endometrium does not have a single, constant function from birth to death The endometrium exists to provide a ‘fertile ground’ for implantation of an embryo and development of a highly invasive placenta, which is achieved by an orderly sequence of development and transformation within each menstrual cycle, under the influence of the ovarian steroid hormones1 The endometrial cells become terminally differentiated during each menstrual cycle; in the absence of conception, tissue shedding and regeneration for subsequent fertile cycles occurs In menstruating species, decidualization is spontaneous, rather than embryo-mediated Decidualization is the process of the transformation or differentiation of human endometrial stromal fibroblasts to secretory ‘epithelioid’ cells, which occurs under the influence of the hormones oestrogen and progesterone, along with cAMP and local paracrine factors The evolution of spontaneous decidualization is thought to have occurred when genes that were ancestrally expressed in other organs and tissue systems were expressed in the endometrium Transposable elements, NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION | d e v r e s e r s t h g i r l l A d e t i m i L s r e h s i l b u P n a l l i m c a M © REVIEWS Key points • The human endometrium is a unique, dynamic tissue that is cyclically shed, repaired, regenerated and remodelled, in preparation for embryo implantation • Decidualization in women occurs spontaneously (regardless of the presence of an embryo) during the mid‑to‑late luteal phase, necessitating endometrial shedding and subsequent regeneration in the absence of conception • Endometrial remodelling occurs primarily under the orchestration of oestrogen and progesterone, but is influenced by many factors, including epigenetic signals and stem/progenitor cells • Abnormalities in endometrial remodelling lead to pathologies including infertility, endometriosis and pregnancy disorders • Understanding the processes that operate in the endometrium could provide information that is applicable to nonreproductive pathologies such as cancer and wound healing for instance, contributed to the origin of decidualization by conferring progesterone responsiveness to numerous genes across the genome2 The evolutionary transformation of the endometrial regulatory landscape has been mapped and found to explain the developments within the human uterus that support its unique pregnancy phenotype, of which decidualization and menstruation are central2 Decidualization probably evolved because it provided protection to uterine tissues from the hyper­ inflammation and oxidative stress associated with deep haemochorial placentation3,4 However, menstruation as a consequence of decidualization is equally important in the human adaptation to haemochorial placentation Repeated cycles of decidualization and shedding prepare human uterine tissues by physiological preconditioning for the stress of haemochorial placentation4 In an adolescent who is pregnant (and has experienced few menstrual cycles), extensive preconditioning has not occurred, which results in a higher risk of major obstetric complications associated with defective placentation than is seen in older pregnant women Menstrual cycles are hypothesized to undergo their own ‘evolution’ throughout the reproductive lifespan, with the endometrium transitioning from a fairly progesteroneresistant, immature tissue at menarche to become more responsive because of the cumulative effects of cyclic menstruation and inflammatory signalling 3,5 The lack of preconditioning and, thus, the absence of these cyclederived changes is proposed to contribute to the aetiology of pregnancy complications in adolescents who have not yet developed progesterone responsiveness This evolution of spontaneous decidualization and menstruation, and the dysfunction associated with these processes, has given rise to human-specific reproductive complications, including recurrent early pregnancy loss and placental pathologies such as pre-eclampsia, in addition to menstrual problems such as heavy or abnormal bleeding Mechanisms of endometrial remodelling Endometrial luminal epithelium The endometrium undergoes substantial remodelling under the influence of ovarian steroid hormones, and becomes receptive for only a few days in the mid-secretory phase of the menstrual cycle (FIG. 1) The luminal epithelium is the first uterine point of contact for blastocysts, and differentiates considerably during the receptive phase to facilitate embryo attachment and subsequent implantation The transformation of the plasma membrane in cells of the luminal epithelium from a nonadhesive to an adhesive surface encompasses remodelling of elements that contribute to the endometrial barrier function, including the glycocalyx, epithelial polarity, epithelial–mesenchymal transition and the lateral junctional complexes (FIG. 1)6 Importantly, in humans the placental trophoblasts invade between epithelial cells, without the epithelial destruction that is observed in other species with haemochorial placentation7 Defects in interactions between embryos and the endometrial epithelium contribute substantially to infertility and implantation failure8 The known molecular changes that occur in human endometrial luminal epithelium in relation to receptivity affect the integrins, osteopontin, Notch signalling, heparin-binding EGF-like growth factor, cell-surfaceassociated mucins, glycodelin and ion channels, which have been reviewed elsewhere9 Some cytokines probably also have important roles in endometrial epithelial receptivity For example, levels of IL‑11 are lower in endometrial luminal epithelium in infertile women than in fertile women10 IL‑11 regulates the adhesiveness of epithelial cells in vitro, probably by upregulating expression of the plasma membrane proteins annexin A2 and flotillin‑111, which are proposed to be essential for receptivity and embryo attachment 11 The results of transcriptomic profiling studies have identified large numbers of genes that are upregulated or downregulated in the induction of receptivity, but data sets vary considerably between studies (as has been reviewed elsewhere12), which suggests post-translational regulation of proteins at the endometrial epithelial surface is important (FIG. 1) Studies on the serine protease proprotein convertase subtilisin/kexin type 5 (PC6) have revealed that, in endometrial epithelium, PC6 is maximally expressed during the receptive phase, but its expression is lower in women with implantation failure than in reproductively healthy women13 PC6, via its proteolytic activity, post-translationally regulates antiadhesion molecules and the organization of the plasma membrane in human endometrial epithelium, altering the apical architecture to provide a receptive surface13,14 Decidualization In human endometrial stromal cells (ESCs), decidualization is the process of spontaneous, terminal differentiation that occurs in the mid‑to‑late secretory phase of each menstrual cycle, whereas in nonmenstruating species, this process is initiated during pregnancy (FIG. 1) In a menstrual cycle that does not result in conception, the terminally differentiated cells are shed during menses However, if pregnancy occurs, decidual cells promote the invasion of fetal extra­villous trophoblasts that (along with uterine natural killer (uNK) cells) facilitate spiral-artery remodelling and protect the conceptus by conferring maternal immunotolerance of the fetal allograft 15 The decidual cells also | ADVANCE ONLINE PUBLICATION www.nature.com/nrendo d e v r e s e r s t h g i r l l A d e t i m i L s r e h s i l b u P n a l l i m c a M © REVIEWS Blastocyst Trophectoderm Glycocalyx Post-translational regulation of the surface molecules Inner cell mass Pinopode Adherens Tight junction junction Cell surface adhesion factors EMT Luminal epithelium Mesenchymal stem cell Differentiation Decidual cell Macrophage Progesterone Glandular epithelium MET Perivascular cell Blood vessel Stromal fibroblast uNK Ovulation 15 16 17 18 19 20 21 22 23 24 25 Day Pre-receptive Receptive Post-receptive Figure | The pre-receptive, receptive and post-receptive endometrium The pre-receptive epithelium (1) is Natureluminal Reviews | Endocrinology nonadhesive, owing to the presence of antiadhesive factors, including the glycocalyx, a polarized epithelium and lateral junctions that anchor cells tightly together During the pre-receptive phase, the glandular epithelium becomes highly secretory (2), uterine natural killer (uNK) cells proliferate and macrophages influx into the endometrium (3) To become receptive, the luminal epithelium undergoes considerable changes (4): epithelial and blastocyst-secreted enzymes post-translationally modify the glycocalyx; the epithelium undergoes epithelial–mesenchymal transition (EMT), becoming less polarized with fewer lateral junctions, and the adhesion-factor repertoire on the luminal epithelial surface changes Pinopodes (5) appear on the surface of the luminal epithelium at the initiation of receptivity, but their role in blastocyst– epithelium adhesion is currently unclear Communication between blastocysts and uterine luminal epithelium further enhances receptivity (6) Decidualization (7) is initiated by progesterone in stromal cells adjacent to blood vessels, and in vascular mesenchymal stem cells These cells undergo mesenchymal–epithelial transition (MET) to become rounded, secretory cells expressing the decidual markers prolactin and insulin-like growth factor-binding protein 1 Decidual cells secrete factors (such as hormones, cytokines, chemokines, lipids and noncoding RNAs) that act synergistically or additively to create a wave of decidualization (8) throughout the endometrium shield the conceptus from environmental stress signals16, and ‘sense’ embryo quality to facilitate maternal rejection of developmentally incompetent embryos17 Progesterone induces decidualization in stromal cells adjacent to spiral arterioles (FIG. 1) In vitro, decidualized stem-cell-like perivascular stromal cells produce higher levels of cytokines and chemokines that are involved in promoting decidualization and the recruitment of trophoblasts than nonperivascular stromal cells16 Decidualization also requires cAMP18, and involves reprogramming of ESCs, which ensures that different genes are expressed at specific stages of differentiation19 After the initiation of decidualization, local paracrine factors create a ‘wave’ of decidualization that spreads from spiral arterioles throughout the endometrium (FIG. 1) Decidual regulation has been investigated predominantly in studies of individual molecules; more comprehensive studies of the proteome and secretome20 NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION | d e v r e s e r s t h g i r l l A d e t i m i L s r e h s i l b u P n a l l i m c a M © REVIEWS and microRNA (miRNA) signature21 of decidualization have not added substantially to the repertoire of processes that are known to be involved in decidualization This repertoire has been reviewed elsewhere22 Although progesterone drives decidualization, other steroid receptors (specifically, oestrogen receptor (ER), glucocorticoid receptor, mineralocorticoid receptor and androgen receptor) also have distinct roles22,23, and might confer specificity of hormone action Few in vitro studies have investigated the role of other cell types in the progress of decidualization The results of studies in mice that lack uterine glands show that these glands are essential for decidualization24, but whether they are similarly important in women is not known Human uterine glands secrete many factors that are known to drive decidualization in vitro, but in vivo secretion of these factors into the stroma has not been confirmed25 Leukocytes, including uNK cells, mast cells, T cells and dendritic cells, are essential for decidual angiogenesis during the initiation of pregnancy (FIG. 1) However, their function in decidualization is less clear Murine models of dendritic-cell depletion indicate that these cells are required for decidual proliferation and differentiation26 Similarly, uNK cells in mice seem to maintain decidual integrity 27 However, the results of both mouse and human in vitro co‑culture experiments with epithelial and stromal cells have not provided evidence that uNK cells initiate or promote decidualization28 Decidual leukocytes have specific phenotypes, and express distinct markers of differentiation and function compared with peripheral leukocytes Decidualized stromal cells secrete mediators that can act on, and influence the function and differentiation of, resident leukocytes29 Menstrual breakdown and repair Menstruation is initiated by the withdrawal of oestrogen and progesterone support in the absence of implantation and pregnancy, and is governed by a complex cascade of endocrine and paracrine signalling within the endometrium (FIG. 2) In macaques, which are menstruating nonhuman primates, the onset of menstruation can be blocked by progesterone replacement within 36 h of hormone withdrawal, but replacement after 36 h has no effect 30 This result suggests a biphasic activation of menstruation, in which endocrine signalling to cells expressing progesterone receptor initiates paracrine signalling to cells without progesterone receptor, which facilitates progesterone-independent effects that lead to menses Intriguingly, endometrial tissue destruction and re‑ epithelialization occur simultaneously; re‑epithelialization is generally considered to start ~36 h after the onset of menses, and is complete within a further 48 h The results of hysteroscopic analysis of the menstrual endometrium emphasize that menstrual shedding is a zonal event; areas undergoing breakdown can be observed adjacent to intact tissues from the previous cycle and areas that have already undergone re-epithelialization31 Decidualized stromal cells (FIG. 1) are essential for responding to endocrine cues and transmitting paracrine signals during menstruation, as they express the progesterone receptor premenstrually 32 and detect progesterone withdrawal33 Hormone withdrawal from decidualized stromal cells in vitro enhances inflammatory reactive oxygen species via inhibition of superoxide dismutase activity, which upregulates nuclear factor κB (NF‑κB) and prostaglandin G/H synthase 2 (PTGS2, also known as COX‑2) signalling relative to levels in the presence of progesterone and results in production of inflammatory factors, including prostaglandin F2α (REFS 33,34) (FIG. 2) Hormone withdrawal triggers the recruitment of inflammatory cells into the perimenstrual endometrium via alterations in chemokines derived from decidualized stromal cells33,35 (FIG. 2) Secretion of proteolytic enzymes by leukocytes results in tissue breakdown at menses, as reviewed elsewhere35, and local tissue lysis simultaneously results in the production of cues for repair 36 Expression of proteases and gene products involved in extracellular matrix synthesis and repair is elevated specifically in stromal cells derived from areas of the endometrium that have undergone lysis36,37 Oestrogen is not required for endometrial repair, as demonstrated by evidence from the study of ovariectomized women and women in natural menopause38 In vitro human studies have defined ‘wound-healing’ factors, including activin, vascular endothelial growth factor (VEGF), cysteine-rich secretory protein 3 and galectin‑7, along with development-related pathways, such as Wnt signalling pathways and mesenchymal–epithelial transition (FIG. 2), which contribute to re‑epithelialization and endometrial wound repair independently of oestrogen 37,39–42 However, once the endometrial surface is re‑epithelialized, oestrogen is required to stimulate glandular and stromal regeneration (FIG. 2) Menstrual endometrium demonstrates the opposing processes of tissue destruction and repair simultaneously in an inflammatory environment; both processes are initiated by similar physiological cues Understanding how the menstrual endometrium limits inflammation, modulates immune-cell activity, rapidly repairs and remains scar-free has implications for the development of treatments for a number of pathologies (BOX 1) Stem/progenitor cells in regeneration Small populations of adult stem/progenitor cells with classic stem-cell properties of clonogenicity, self-renewal and differentiation have been identified in human endometrium43 (TABLE 1); these cells contribute to the ability of the endometrium to regenerate during each menstrual cycle (FIG. 2) Specific stem/progenitor cell types, including epithelial progenitors, mesenchymal stem cells and side-population cells (which are characterized by the efflux of DNA-binding dyes, a universal property of adult stem cells) might be involved in the regeneration of different endometrial cellular compartments43 Epithelial progenitor cells have been identified in human endometrium as clonogenic cells that differentiate into large, gland-like structures44, and in mice as label-retaining cells that proliferate in response to oestrogen, despite lacking ERs (TABLE 1) ERα-expressing niche cells that are closely associated with epithelial progenitor cells probably transmit the oestrogen signal | ADVANCE ONLINE PUBLICATION www.nature.com/nrendo d e v r e s e r s t h g i r l l A d e t i m i L s r e h s i l b u P n a l l i m c a M © REVIEWS Uterine bleeding Late secretory (days 24–28) • No conception • Corpus luteum demise • Hormone withdrawal Luminal epithelium Repair (days 2–5) • Chemokines • Growth factors • Wnt signalling • MET Regeneration (days 5–14) • Epithelial progenitor cells • Mesenchymal stem cells • Wnt signalling • Notch signalling 11 Blood vessel Tissue destruction NF-κB COX-2 Growth factor activation • Growth factors • Chemokines Endometrial growth Vasoconstriction • PGE2 • PGF2α 10 Stromal fibroblast Decidualized stromal cell Menstruation (days 1–5) Proteolytic enzymes Functionalis Basalis Eosinophil Neutrophil Macrophage Perivascular cell Epithelial progenitor cell Mesenchymal stem cell Figure | Endometrial decidualization, menstruation, repair and regeneration Endometrial (1) and Naturestromal Reviewscells | Endocrinology mesenchymal stem cells (2) undergo decidualization under the influence of oestrogen and progesterone In the absence of conception and implantation (3), endometrial stromal cells ‘sense’ hormone withdrawal upon the demise of the corpus luteum, and upregulate intracellular inflammatory signalling (4) and the release of inflammatory factors that contribute to vasoconstriction of uterine blood vessels (5), recruitment of leukocytes (6) and propagation of the menstrual cascade However, these inflammatory and growth factors (4), proteolytic enzymes (7) and recruited immune cells (8) also contribute to repair after menstruation, in concert with processes such as mesenchymal–epithelial transition (MET) (9) and Wnt signalling, to restore endometrial homeostasis (10) Activation of endometrial epithelial progenitor cells and perivascular mesenchymal stem cells (11), possibly involving Wnt signalling or Notch signalling, drives cellular replacement in the glands and stroma respectively, to mediate regeneration of the endometrium COX‑2, prostaglandin G/H synthase 2 (PTGS2); NF‑κB, nuclear factor κB to these ERα-negative cells Epithelial progenitors are thought to be located in the basalis region of the uterine glands (FIG. 1), where a high level of telomerase activity (a feature of adult stem cells) has been detected43 Specific markers identifying epithelial progenitor cells are required to facilitate delineation of their role in endometrial proliferative disorders (BOX 2) Human endometrium also contains a small population of mesenchymal stem cells (eMSCs)43 (TABLE 1) Specific surface markers of clonogenic eMSCs demonstrate their perivascular localization in the endometrial functionalis and basalis45,46 (FIG. 1), as well as their presence within shed fragments in menstrual fluid43 eMSCs have been identified by the co‑expression of CD146 and plateletderived growth factor receptor β (PDGFRβ) markers as pericytes45 A single marker, sushi domain-containing protein 2 (SUSD2, also known as W5C5)) identified 4% of endometrial stromal cells in 34 samples of stromal cells as eMSCs46 (TABLE 1) Gene profiling of fresh CD146+PDGFRβ+ cells47 and cultured SUSD2+ cells16 confirmed that eMSCs have a pericytic, perivascular signature, which suggests that eMSCs have an additional role in angiogenesis during stromal regeneration and placentation43 These endometrial perivascular cells are distinct from the stromal fibroblast (CD146−PDGFRβ+) and endothelial (CD146+PDGFRβ−) populations47 Side-population cells48 are also present within human endometrium; these populations are a mix of ERβexpressing endothelial cells with some epithelial and stromal cells that not express ERα or progesterone receptor 49,50 (TABLE 1) In xenografts, the side-population cells regenerate human ‘endometrium’ consisting mainly NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION | d e v r e s e r s t h g i r l l A d e t i m i L s r e h s i l b u P n a l l i m c a M © REVIEWS Box | Translating endometrial biology to other pathologies Skin wounds Chronic skin wounds commonly exhibit deficient re‑epithelialization Understanding how the endometrium undergoes rapid repair after menstruation could lead to novel insights into the development of treatments to promote repair of chronic wounds Chronic inflammatory diseases The endometrium limits inflammation during menstruation to prevent excessive tissue destruction Translating the mechanism by which inflammation is restricted could aid the resolution of chronic inflammation Stem-cell dysfunction Cyclic activation of stem cells is required for endometrial regeneration after menstruation This process occurs monthly for an average of 450 menstrual cycles, but stem-cell senescence occurs in women with recurrent pregnancy loss Delineation of the factors and mechanisms involved in cyclic activation could aid the treatment of recurrent pregnancy loss and other diseases associated with stem-cell dysfunction Fibrotic diseases Repair of the endometrium following menstrual shedding is scar-free Understanding how the endometrium remains scar-free despite inflammation and tissue destruction each month could lead to novel therapies for fibrosis of stromal and vascular tissue, with occasional epithelial gland-like structures49–51 Similarly, SUSD2+ eMSCs generate stromal tissue in xenografts46 However, in human endometrium in  vivo, whether one or more stem/ progenitor cell type regenerates endometrial tissue, or a stem/progenitor cell hierarchy exists, is not known In an experimental model of wound repair, eMSCs modulated chronic inflammation outside the uterus, which suggests these cells have a role in communication and regulation of macrophages52 Determination of the function of these cells in endometrial physiology has the potential to identify their roles in endometrial disorders (BOX 2) Endometrium–embryo crosstalk The pre-implantation microenvironment Uterine fluid provides the natural environment for sperm transport and blastocyst hatching together with pre-implantation development, as well as peri-implantation embryonic– maternal interactions The fluid contains not only the nutrients necessary for blastocyst growth, but also important regulatory molecules and microvesicles53 Specific proteins secreted from the endometrium interact with the blastocyst to facilitate implantation25,54,55 (FIG. 1) mi­­RNAs in uterine fluid are taken up by preimplantation mouse embryos and alter embryonic mRNA expression in vitro 56 Uterine fluid must also contain factors to protect the mother and embryo from bacteria and other pathogens57 Many classes of molecules, from simple salts and amino acids through to proteins, steroids and lipids are contained in uterine fluid These molecules are derived from multiple sources, including endometrial epithelial secretions, selective transudation from blood, leukocyte activation and possibly Fallopian tubal secretions and peritoneal fluid Glucose, lactate and pyruvate are required for human blastocyst development58 Alterations in the levels of these factors might also alter the pH of the local environment Proteins in uterine fluid include leukaemia inhibitory factor (LIF), VEGF, IL‑11 and other chemokines and cytokines that are probably synthesized in the endometrium and secreted into the uterine cavity 54, establishing a complex milieu to facilitate implantation The amino acid profile of uterine fluid has been determined, but the full molecular composition is not yet known59 The mechanisms involved in the regulation of levels of nutrients and ions, and the relationships between these components and their relative importance in the establishment of pregnancy, are still to be determined Blastocysts and endometrial epithelium Successful implantation and pregnancy outcome require both a receptive endometrium and an appropriately developed blastocyst Blastocysts enter the uterine cavity during the receptive phase and remain for up to 72 h before implantation (FIG. 1) After blastocyst hatching from the zona pellucida, the trophectoderm comes into close contact with, and firmly adheres to, the receptive endometrial luminal epithelium, which initiates implantation (FIG. 1) The influence of blastocysts on receptivity and implantation is poorly defined in humans, although hormonal, epigenetic and metabolomic cues have been identified Blastocysts communicate with the endometrium via cell-surface proteins and secreted factors60 (FIG. 1) Human chorionic gonadotropin (hCG) is secreted by hatched human blastocysts in close apposition to the endometrial epithelium61 Treatment of primary human endometrial epithelial cells (EECs) with hCG, as well as infusion of hCG into the uterine cavity of humans and baboons, mediates the production of factors that are associated with endometrial receptivity, including LIF, VEGF, IL‑11 and prokineticin‑1 (REFS 62–65) Human blastocysts require glucose metabolism, but exhibit an idiosyncratic metabolic mechanism that produces high levels of lactate in close proximity to the uterine epithelium, creating a low pH environment 66 This process is thought to promote local endometrial tissue disaggregation, facilitating trophectoderm cell invasion into the endometrium via modulation of epithelial VEGF production54 Human blastocysts regulate EEC adhesion and gene expression via secreted regulators67 Culture media derived from blastocysts generated by in vitro fertilization (IVF) that subsequently implant (resulting in a live birth) enhance primary human EEC adhesion, unlike IVF blastocysts that not successfully implant 68 Human blastocysts that are determined by morphology to be of high quality during IVF culture, but that not subsequently implant after transfer, secrete mi­­RNAs that are not secreted by blastocysts that implant 68 mi­­RNAs secreted by IVF blastocysts during culture might reflect their quality and implantation potential.miR‑661, bound to the RNA-binding protein argonaute‑1, is secreted specifically by human IVF blastocysts that not implant68 miR‑661 is also taken up by primary human EECs in culture and blocks their adhesive capacity 68,69 This antiadhesion effect of miR‑661 is mediated, at least in part, by downregulation of the production of nectin‑1 in primary human EECs68 | ADVANCE ONLINE PUBLICATION www.nature.com/nrendo d e v r e s e r s t h g i r l l A d e t i m i L s r e h s i l b u P n a l l i m c a M © REVIEWS Table | Properties of endometrial stem/progenitor cells Stem/progenitor Stem-cell property cell Cell types and markers Frequency among endometrial cells Clonogenic cells (human) Ability of a single cell to form a colony when seeded at low density in culture Epithelial progenitor cells [...]... expression in differentiating human endometrial stromal cells Endocrinology 140, 4809–4820 (1999) 19 Popovici, R. M et al Gene expression profiling of human endometrial- trophoblast interaction in a coculture model Endocrinology 147, 5662–5675 (2006) 20 Garrido-Gomez, T et al Modeling human endometrial decidualization from the interaction between proteome and secretome J. Clin Endocrinol Metab 96, 706–716... roles in many processes including cell‑to‑cell communication155 and immune regulation156 Extracellular vesicles are present in human uterine lavage and aspirate56,157, and are released from both primary EECs56 and EEC lines157–159 Analysis of a murine endometrial miRNA (hsa-miR‑30d) showed that it was maximally expressed in the mid-secretory phase, and was taken up by mouse-embryo trophectoderm and by... Uterine DCs are crucial for decidua formation during embryo implantation in mice J. Clin Invest 118, 3954–3965 (2008) 27 Ashkar, A. A., Di Santo, J. P & Croy, B. A Interferon γ contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy J. Exp Med 192, 259–270 (2000) 28 Gong, X et al Insights into the paracrine... fetal-maternal dialogue regulating endometrial leukemia inhibitory factor FASEB J 23, 2165–2175 (2009) 63 Licht, P., Fluhr, H., Neuwinger, J., Wallwiener, D & Wildt, L Is human chorionic gonadotropin directly involved in the regulation of human implantation? Mol Cell Endocrinol 269, 85–92 (2007) 64 Paiva, P et al Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial... and Dicer requirement during human endometrial stromal decidualization in vitro PLoS ONE 7, e41080 (2012) 22 Gellersen, B & Brosens, J. J Cyclic decidualization of the human endometrium in reproductive health and failure Endocr Rev 35, 851–905 (2014) 23 Kuroda, K et al Induction of 11β‑HSD 1 and activation of distinct mineralocorticoid receptor- and glucocorticoid receptor-dependent gene networks in. .. interleukin 11 regulated plasma membrane proteins in human endometrial epithelial cells in vitro Reprod Biol Endocrinol 9, 73–87 (2011) 12 Haouzi, D., Dechaud, H., Assou, S., De Vos, J & Hamamah, S Insights into human endometrial receptivity from transcriptomic and proteomic data Reprod Biomed Online 24, 23–34 (2012) 13 Heng, S., Hannan, N. J., Rombauts, L. J., Salamonsen, L. A & Nie, G PC6 levels in uterine...REVIEWS Noncoding RNA could also contribute to endometrial remodelling and endometrial disorders Noncoding RNAs are classified according to their size, structure and regulatory properties, from long noncoding RNA (lncRNA) >200 nucleotides to small or medium noncoding RNA, including miRNA of 18–20 nucleotides145 The mi­­RNAs are the most well studied noncoding RNAs in the endometrium, and their expression... which indicates that they are subject to hormonal regulation Some mi­­RNAs are released into the uterine cavity 56, and are potential markers of receptivity and the phase of the cycle Endometrial miRNA expression profiles are altered in women with infertility, endometriosis, recurrent miscarriage146–148 and implantation failure149 In addition, mi­­RNAs are involved in regulating decidualization, and. .. gene networks in decidualizing human endometrial stromal cells Mol Endocrinol 27, 192–202 (2013) 24 Filant, J & Spencer, T. E Endometrial glands are essential for blastocyst implantation and decidualization in the mouse uterus Biol Reprod 88, 93 (2013) 25 Filant, J & Spencer, T. E Uterine glands: biological roles in conceptus implantation, uterine receptivity and decidualization Int J. Dev Biol 58, 107–116... Insulin resistance does not affect early embryo development but lowers implantation rate in in vitro maturation in vitro fertilization-embryo transfer cycle Clin Endocrinol (Oxf.) 79, 93–99 (2013) 110 Ujvari, D et al Lifestyle intervention up‑regulates gene and protein levels of molecules involved in insulin signaling in the endometrium of overweight/ obese women with polycystic ovary syndrome Hum Reprod ... cells expressing the decidual markers prolactin and insulin-like growth factor-binding protein 1 Decidual cells secrete factors (such as hormones, cytokines, chemokines, lipids and noncoding RNAs)... and women in natural menopause38 In vitro human studies have defined ‘wound-healing’ factors, including activin, vascular endothelial growth factor (VEGF), cysteine-rich secretory protein 3 and. .. oestrogen and progesterone, but is influenced by many factors, including epigenetic signals and stem/progenitor cells • Abnormalities in endometrial remodelling lead to pathologies including infertility,